US7994220B2 - Milnacipran for the long-term treatment of fibromyalgia syndrome - Google Patents

Milnacipran for the long-term treatment of fibromyalgia syndrome Download PDF

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US7994220B2
US7994220B2 US11/535,237 US53523706A US7994220B2 US 7994220 B2 US7994220 B2 US 7994220B2 US 53523706 A US53523706 A US 53523706A US 7994220 B2 US7994220 B2 US 7994220B2
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milnacipran
pain
fms
fibromyalgia
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Srinivas G. Rao
Michael Gendreau
Jay D. Kranzler
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the long-term treatment of fibromyalgia and its symptoms by administering to a patient suffering from fibromyalgia a dual norepinephrine serotonin reuptake inhibitor. More particularly, the present invention relates to the long-term treatment of fibromyalgia and its symptoms by administering to a patient suffering from fibromyalgia a dual norepinephrine serotonin reuptake inhibitor that inhibits the reuptake of norepinephrine to an equal or greater extent than it inhibits the reuptake of serotonin.
  • Fibromyalgia also known as the fibromyalgia syndrome (FMS) is a common systemic rheumatologic disorder estimated to affect 2% to 4% of the population, second in prevalence among rheumatologic conditions only to osteoarthritis.
  • FMS fibromyalgia syndrome
  • Fibromyalgia is associated with a reduced threshold for pain, generally identified by an increased sensitivity to pressure all over the body, and is often accompanied by fatigue, sleep disturbance, and morning stiffness.
  • Other common symptoms include headache, migraine, variable bowel habits, diffuse abdominal pain, and urinary frequency.
  • fibromyalgia require not only a history of widespread pain, but also the finding of tenderness on physical examination (“tender points”).
  • tender points In order to fulfill the criteria for fibromyalgia established in 1990 by the American College of Rheumatology (ACR), an individual must have both widespread pain involving all four quadrants of the body as well as the axial skeleton and the presence of 11 of 18 tender points on examination.
  • ACR American College of Rheumatology
  • FMS central nervous system
  • FMS patients typically suffer from both allodynia (perceiving pain even from a non-painful stimulus such as light touch) and hyperalgesia (an augmentation of pain processing in which a painful stimulus is magnified and perceived with higher intensity than it would be by a normal volunteer).
  • allodynia perceiving pain even from a non-painful stimulus such as light touch
  • hyperalgesia an augmentation of pain processing in which a painful stimulus is magnified and perceived with higher intensity than it would be by a normal volunteer.
  • neuropathic pain such as diabetic neuropathy and trigeminal neuralgia.
  • Fibromyalgia is also associated with high rates of disability, increased health care utilization, more frequent psychiatric consultations and a greater number of lifetime psychiatric diagnoses than controls.
  • Fibromyalgia research has recently emerged as a significant area of investigation separate from the study of other chronic pain conditions.
  • a significant body of literature already supports the use of tricyclic antidepressants for FMS, and there are a few other controlled studies evaluating the efficacy of other therapeutic agents as well.
  • the interpretation of trial data is complicated by factors such as the lack of an accepted binary definition of a “responder” versus a “non-responder,” as is now commonly used for trials of other rheumatological conditions, such as Rheumatoid Arthritis.
  • Felson et al. Arthritis Rheum. 1993; 36(6):729-740
  • Felson D T J Rheumatol. 1993; 20(3):581-534.
  • Non-steroidal anti-inflammatory drugs and acetaminophen are also used by a large number of patients (Wolfe et al., Arthritis Rheum. 1997; 40(9):1571-1579), even though peripheral inflammation has not been demonstrated (Clauw D J and Chrousos G P, Neuroimmunomodulation 1997; 4(3):134-153), and numerous studies have failed to confirm their effectiveness as analgesics in FMS.
  • Goldenberg et al. Arthritis Rheum. 1986; 29(11):1371-1377; Yunus et al., J Rheumatol. 1989; 16(4):527-532; Wolfe et al., Arthritis Rheum.
  • Antidepressants of all varieties represent a common form of therapy for many chronic pain states, including FMS. Sindrup S H and Jensen T S, Pain 1999; 83(3):389-400; Buskila D, Baillieres Best Pract Res Clin Rheumatol. 1999; 13(3):479-485; Leventhal L J, Ann Intern Med. 1999; 131(11):850-858; Lautenschlager J, Scand J Rheumatol Suppl. 2000; 113:32-36; Bennett R M, J Functional Syndromes 2001; 1(1):79-92.
  • the majority of available antidepressants directly and/or indirectly increase the levels of 5-HT and/or NE in the CNS. Monoaminergic levels are increased either by inhibiting re-uptake (by blocking transport proteins) or interfering with the breakdown of the monoamine (by inhibiting the monoamine oxidase enzymes) after its release into the synaptic cleft.
  • TCAs Tricyclic Antidepressants
  • TCAs most commonly employed in the treatment of FMS include amitriptyline, doxepin, and cyclobenzaprine.
  • Buskila D Baillieres Best Pract Res Clin Rheumatol. 1999; 13(3):479-485; Lautenschlager J, Scand J Rheumatol Suppl. 2000; 113:32-36; Bennett R M, J Functional Syndromes 2001; 1(1):79-92.
  • cyclobenzaprine is typically classified as a muscle relaxant, rather than an antidepressant, it shares structural and pharmacological similarities with the TCAs, although its sedating qualities often override its usefulness in other applications.
  • Kobayashi et al. Eur J Pharmacol.
  • TCAs block the re-uptake of both 5-HT and NE, but favor NE re-uptake blockade, and the efficacy of TCAs can be interpreted to support the primacy of NE agonism for analgesic activity.
  • TCA's additional anti-cholinergic, antihistaminergic, and ⁇ -adrenergic receptor blockade activities impart a wide assortment of undesirable side effects, which often compromise their tolerability and clinical acceptance. Kent J M, Lancet 2000; 355(9207):911-918.
  • TCAs have demonstrated moderate efficacy for the treatment of neuropathic pain conditions such as post-herpetic neuralgia and painful diabetic neuropathy.
  • neuropathic pain conditions such as post-herpetic neuralgia and painful diabetic neuropathy.
  • Multiple studies of TCAs in the treatment of FMS support their use for this syndrome as well, and TCAs have frequently been used as the positive controls to which newer agents have been compared.
  • SSRIs Selective Serotonin Re-Uptake Inhibitors
  • the SSRIs have revolutionized the treatment of depression with their improved side-effect profile secondary to more selective re-uptake inhibition.
  • the SSRI agents fluoxetine, sertraline and citolopram have each been evaluated in randomized, placebo controlled trials in FMS. Goldenberg et al., Arthritis & Rheumatism 1996; 39(11):1852-1859; Wolfe et al., Scand J Rheum. 1994; 23(5):255-259; Anderberg et al., Eur J Pain 2000; 4(1):27-35; Norregaard et al., Pain 1995; 61(3):445-449.
  • the results of these trials have been somewhat inconsistent, leaving much debate regarding the relative efficacy of the SSRIs, especially in comparison to TCAs.
  • Dual re-uptake inhibitors are pharmacologically similar to TCAs (such as amitriptyline and doxepin), exhibiting activity upon both 5-HT and NE re-uptake. Sanchez C and Hytell J, Cell Mol Neurobiol. 1999; 19(4):467-489. Fortunately, these newer agents are generally devoid of significant activity at other receptor systems, resulting in diminished side effects and enhanced tolerability vs. TCA's. Therefore, this class of antidepressant may have significant potential for the treatment of FMS and/or other chronic pain conditions.
  • DRIs that are commercially available in the U.S. include venlafaxine and duloxetine. A number of DRIs are in clinical development; these include milnacipran, bicifadine, viloxazine, LY-113821, SEP-227162, AD-337, and desvenlafaxine succinate (DVS-233).
  • Opiates exert their anti-nocioreceptive effects at various locations within both the ascending and descending pain pathways. Duale et al., Neuroreport 2001; 12(10):2091-2096; Besse et al., Brain Res. 1990; 521(1-2):15-22; Fields et al., Nature 1983; 306(5944):684-686; opioids in chronic pain conditions are widely discussed and debated. Bennett R M, J Functional Syndromes 2001; 1(1):79-92. However, opioids are used by some in the clinical management of FMS, especially when other analgesics have failed to provide sufficient relief. Bennett R M, Mayo Clin Proc. 1999; 74(4):385-398.
  • a DRI may be used to provide effective long-term (e.g., at least three months) treatment for fibromyalgia and its symptoms in patients suffering from fibromyalagia. Further, the results of this clinical study surprisingly showed that a DRI may be used to provide effective, long-term treatment of FMS and its symptoms for at least 6 months.
  • the present invention provides methods of long-term treatment of fibromyalgia syndrome in a patient in need thereof comprising administering a DRI to the patient for at least three months.
  • the DRI is a compound that inhibits norepinephrine reuptake more than or equal to serotonin reuptake (NSRI).
  • NSRI serotonin reuptake
  • the NSRI is milnacipran.
  • long-term treatment of FMS and its symptoms may be provided to a patient suffering from FMS by administering 25 mg per day to 400 mg per day of milnacipran.
  • milnacipran may be administered in a dose of 100 mg per day for the long-term treatment of FMS and its symptoms in a patient suffering from FMS.
  • milnacipran may be administered in a dose of 200 mg per day for the long-term treatment of FMS and its symptoms in a patient suffering from FMS.
  • FIG. 1 is a timeline of the clinical study described in Example 1.
  • FIG. 2 is a bar graph which illustrates the percentage of responders at 3 months and 6 months for the placebo, milnacipran 100 mg/day and milnacipran 200 mg/day groups described in Example 1.
  • the term “subject” or “patient” includes human and non-human mammals.
  • treatment means to relieve, alleviate, delay, reduce, reverse, improve or prevent at least one symptom of fibromyalgia.
  • DRI dual reuptake inhibitor
  • NSRI Norepinephrine-serotonin reuptake inhibitor
  • SNRI Serotonin-norepinephrine reuptake inhibitor
  • DRI compounds that block the reuptake of norepinephrine preferentially are referred to as NSRI's, whereas those that preferentially block the reuptake of serotonin are referred to as SNRI's.
  • Common DRI compounds include, but are not limited to, the SNRI's venlafaxine and duloxetine, and the NSRI's bicifadine and milnacipran.
  • NSRI compounds are described in detail in U.S. Pat. No. 6,602,911, the contents of which are hereby incorporated by reference in their entirety.
  • the present invention provides methods of long-term treatment of fibromyalgia syndrome in a patient comprising administering a DRI to a patient in need thereof for at least three months.
  • the DRI compounds are NSRI's.
  • the NSRI is milnacipran.
  • milnacipran may be administered as a hydrochloride salt: Z-2-aminomethyl-1-phenyl-N,N-diethylcyclopropanecarboxamide hydrochloride (chemical formula C 15 H 23 ClN 2 O).
  • milnacipran may be administered as a mixture of the dextro- and levrogyral enantiomers, e.g., as a mixture that includes more of one enantiomer or as a racemic mixture.
  • milnacipran may be administered in an enantiomerically pure form (e.g., as the pure dextro- or pure levrogyral enantiomer).
  • milnacipran can include all stereoisomeric forms, mixtures of stereoisomeric forms, diastereomeric forms, and pharmaceutically acceptable salts thereof, including both enantiomerically pure forms of milnacipran as well as mixtures of milnacipran enantiomers.
  • compositions suitable for use in the present invention include compositions wherein the active ingredient is contained in a therapeutically or prophylactically effective amount, i.e., in an amount effective to achieve therapeutic or prophylactic benefit for the long-term treatment of FMS and its symptoms. Determination of an effective amount is well within the capabilities of those skilled in the art, especially in light of the disclosure herein.
  • DRI compounds typically range from about 1 ⁇ g to 1 gm/day.
  • the amount of the DRI compound administered to practice the methods of the invention will, of course, be dependent on the DRI, the subject being treated, the severity of the affliction, and the manner of administration. See, e.g., U.S. application Ser. No. 10/678,767, the contents of which are hereby incorporated by reference in its entirety.
  • therapeutically effective amounts can be determined from human data of DRI compounds used to treat depression.
  • the therapeutically effective amount may be the same amount administered to treat depression or can be an amount higher or lower than the amount administered to treat depression.
  • the amount of milnacipran administered to treat depression may be in the range of about 50 mg to about 400 mg/day.
  • about 50 mg to about 400 mg/day of milnacipran may be used for the long-term treatment of FMS and its symptoms.
  • Dosages lower than about 50 mg/day of milnacipran may also be used for the long-term treatment of FMS and its symptoms.
  • the dosage range is typically from 25 mg-400 mg/day, more typically from 100 mg-250 mg/day.
  • the dosage may be administered once per day or several or multiple times per day.
  • Therapeutically effective amounts for use in humans can also be determined from animal models.
  • a dose for humans can be formulated to achieve circulating concentration that has been found to be effective in animals.
  • Useful animal models of pain are well known in the art. For example, models of neuropathic pain are described in Zeltser et al., 2000, Pain 89:19-24; Bennett et al., 1988, Pain 33:87-107; Seltzer et al., 1990, Pain 43:205-218; Kim et al., 1992, pain using complete Freund's adjuvant is described in Jasmin et al., 1998, Pain 75: 367-382.
  • the stress-induced hyperalgesia model described in Quintero et al., 2000, Pharmacology, Biochemistry and Behavior 67:449-458 may be used as an animal model of FMS and CFS.
  • the route of administration of the pharmaceutical compositions of the present invention may be, for example, oral, enteral, intravenous, and transmucosal (e.g., rectal).
  • a preferred route of administration is oral.
  • Pharmaceutical compositions suitable for oral administration can be in the form of tablets, capsules, pills, lozenges, powders or granules, or solutions or dispersions in a liquid. Each form will comprise a predetermined amount of a compound of the invention as an active ingredient.
  • the compositions may be prepared as a tablet employing any pharmaceutical excipient known in the art for that purpose, and conventionally used for the preparation of solid pharmaceutical compositions.
  • the examples of such excipients include, but are not limited to, starch, lactose, microcrystalline cellulose, magnesium stearate.
  • Binders, such as polyvinylpyrrolidone may also be used in the compositions of the present invention.
  • an active compound can be formulated as controlled-release preparation, such as tablets comprising a hydrophilic or
  • compositions of the present invention may be in the form of capsules formulated using conventional procedures, for example by incorporation of a mixture of an active compound and excipients into a hard gelatin capsule.
  • a semi-solid matrix of an active compound and high molecular weight polyethylene glycol may be formed and filled into hard gelatin capsules, or soft gelatin capsules may be filled with a solution of an active compound in polyethylene glycol or dispersion thereof in edible oil.
  • Powder forms for reconstitution before use for example lyophilized powders
  • oily vehicles that may be used as injectable formulations may be used as well.
  • Liquid forms for parenteral administration may also be formulated for administration by injection or continuous infusion.
  • Accepted routes of administration by injection are intravenous, intraperitoneal, intramuscular and subcutaneous.
  • a typical composition for intravenous injection comprises a sterile isotonic aqueous solution or dispersion, including, for example, an active compound and dextrose or sodium chloride.
  • suitable excipients are lactated Ringer solution for injections, lactated Ringer solution for injections with dextrose, Normosol-M with dextrose, acylated Ringer solution for injections.
  • the injection formulation can optionally include co-solvents (e.g., polyethylene glycol), chelating agents (e.g., ethylenediaminotetraacetic acid), stabilizing agents (e.g., cyclodextrin) and/or antioxidants (e.g., sodium pyrosulfate).
  • co-solvents e.g., polyethylene glycol
  • chelating agents e.g., ethylenediaminotetraacetic acid
  • stabilizing agents e.g., cyclodextrin
  • antioxidants e.g., sodium pyrosulfate
  • the DRI may be administered adjunctively with other active compounds for the long-term treatment of fibromyalgia syndrome.
  • active compounds that may be administered include antidepressants, analgesics, muscle relaxants, anorectics, stimulants, antiepileptic drugs, beta blockers, and sedative/hypnotics.
  • DRI DRI-delta ligand
  • modafinil gabapentin, pregabalin, XP13512, pramipexole, 1-DOPA
  • amphetamine tizanidine
  • clonidine tramadol
  • morphine tricyclic antidepressants
  • codeine cambamazepine
  • sibutramine sibutramine
  • valium trazodone
  • caffeine nicergoline
  • bifemelane propranolol
  • atenolol and combinations thereof.
  • the DRI may be milnacipran and may be adjunctively administered with an alpha-2-delta ligand such as, for example, pregabalin.
  • adjunctive administration includes simultaneous administration of the compounds in the same dosage form, simultaneous administration in separate dosage forms, and separate administration of the compounds.
  • milnacipran may be simultaneously administered with valium, wherein both milnacipran and valium are formulated together in the same tablet.
  • milnacipran may be simultaneously administered with valium, wherein both the milnacipran and valium are present in two separate tablets.
  • milnacipran may be administered first followed by the administration of valium, or vice versa.
  • Milnacipran monotherapy for the treatment of fibromyalgia has been previously described in a Phase II trial of 125 fibromyalgia patients. See, e.g., U.S. application Ser. No. 10/678,767, the contents of which are hereby incorporated by reference in its entirety.
  • milnacipran was administered once or twice daily in a dosage escalation regimen to a maximum dose of 200 mg/day.
  • milnacipran provided effective acute (short-term) therapy for symptoms of FMS.
  • twice-daily (BID) and once-daily (QD) dosing of milnacipran were approximately equally effective on fatigue, mood, global wellness, and function.
  • the patient global impression of change (PGIC) outcome measure showed that over 70% of completers in both milnacipran treatment groups reported an improvement in their overall status, while only 10% reported worsening. In contrast, 40% of the placebo patients who completed the trial rated themselves as worse at endpoint. The differences between placebo and milnacipran on the PGIC were statistically significant, both in terms of a comparison of mean endpoint scores, as well as on a binary improved/not-improved basis.
  • milnacipran was an effective acute (short-term) therapy for the symptom of pain in FMS, and milnacipran dosed either once or twice daily had measurable beneficial effects on a wide range of symptoms of FMS, including fatigue (measured on the FIQ), pain (multiple measures), quality of life (multiple measures), and, potentially, mood (Beck instrument).
  • milnacipran or any other active agent, is effective for the long-term (greater than three months) treatment of FMS and its symptoms.
  • the clinical study described in Example 1 below provides the first, and surprising, report of effective long-term treatment of FMS using a NSRI.
  • the primary objective of this study was to demonstrate safety and efficacy, both clinical and statistical, of milnacipran in the treatment of the fibromyalgia syndrome.
  • the primary outcome was a composite responder analysis assessing response rate at weeks 14 and 15, and the secondary analysis assessed response rate at weeks 26 and 27.
  • FIG. 1 A timeline of the study is provided in FIG. 1 .
  • PGIC patient global impression of change
  • FIQ Fibromyalgia Impact Questionnaire
  • FMS Status Assessments Patient pain 24 hour and 7 day recall VAS, the SF-36, Multiple Ability Self-report Questionnaire (MASQ, cognitive function), the Multidimensional Health Assessment Questionnaire (MDHAQ) and the Multi-dimensional Fatigue Inventory (MFI).
  • Diary assessments include current pain (morning, random daily, and evening reports); daily recall pain (morning report); medications taken (evening report); overall pain past week (weekly report), overall fatigue in the last week (weekly report), and the extent that pain kept the patient from caring for themselves (weekly report).
  • the primary endpoint of this study was a composite responder analysis implementing analysis of three domains of interest, evaluated at 24 weeks as the primary analysis, and 12 weeks as the secondary analysis.
  • the domains measured were:
  • the pain domain score was determined by a calculation that compared the average of treatment weeks 14 and 15 to the two baseline weeks, and treatment weeks 26 and 27 vs. baseline for the secondary analysis. The last observation was carried forward if neither the week 14 nor week 15 (or week 26/27) patient self-reported pain score is available to compare to the baseline value.
  • the binary response rate for placebo (based on the composite endpoint) in this study was expected to be in the range of 10-13%, with a milnacipran response rate in the active arm(s) expected in the 27-29% range on an ITT/LOCF basis. Based on these response rate assumptions, 125 patients randomized per arm (250 for high dose group) has been calculated to be the maximum sample size required (90% power). Secondary analyses included total area under the curve of pain intensity, and patient-reported weekly pain recall at the clinic visits as well as the FMS status assessments, and QOL measures.
  • a responder was defined as a subject who experienced a greater than 30% reduction in pain from baseline and improvement on the PGIC.
  • LOCF Last Observation Carried Forward
  • BOCF Baseline Observation Carried Forward
  • OC study completer
  • n number of patients having adequate date for OC analysis (completers of landmark endpoint with observed values for responder assessment).

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